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Differentiation of Human Neuroblastoma Cells: Marked Potentiation of Prostaglandin E-Stimulated Accumulation of Cyclic AMP by Retinoic Acid

Authors

  • Victor C. Yu,

    1. Departmenis of Pharmacy and Pharmaceutical Chemistry, School of Pharmacy, San Francisco
    2. Neurex Corporation, Menlo Park, California, U.S.A.
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  • Güinther Hochhaus,

    1. Departmenis of Pharmacy and Pharmaceutical Chemistry, School of Pharmacy, San Francisco
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  • Fu-Hsiung Chang,

    1. Department of Pharmacology, School of Medicine, University of California, San Francisco
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  • Mark L. Richards,

    1. Departmenis of Pharmacy and Pharmaceutical Chemistry, School of Pharmacy, San Francisco
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    • Dr. M. L. Richards is Medical Biology Institute, 11077 N. Torrey Pines Rd., La Jolla, CA 92037, U.S.A.

  • Henry R. Bourne,

    1. Department of Pharmacology, School of Medicine, University of California, San Francisco
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  • Wolfgang Sadée

    Corresponding author
    1. Departmenis of Pharmacy and Pharmaceutical Chemistry, School of Pharmacy, San Francisco
      Address correspondence and reprint requests to Dr. W. Sadée at School of Pharmacy, UCSF, San Francisco, CA 94143, U.S.A.
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Address correspondence and reprint requests to Dr. W. Sadée at School of Pharmacy, UCSF, San Francisco, CA 94143, U.S.A.

Abstract

Abstract: Neuroblastoma cells in culture contain low levels of cyclic AMP, a second messenger which plays a major role in neuronal maturation. In this study, human neuroblastoma cells, SK-N-SH-SY5Y, were induced to differentiate by treatment with either nerve growth factor (50 ng/ml), retinoic acid (10 μM), dibutyryl cyclic AMP (1 mM), or 12-O-tetradecanoylphorbol-13-acetate (0.1 μM), and the ability of several neurotransmitters or hormones to stimulate adenylyl cyclase was tested. Although all four differentiation factors caused morphological changes towards a neuronal phenotype, only retinoic acid dramatically enhanced cyclic AMP accumulation, specifically upon stimulation with prostaglandin E1 (PGE,). PGE2 was also active, but less potent, than PGE1, whereas the other cyclic AMP-stimulating agents tested were largely unaffected. Further, the rapid desensitization of the PGE1-cyclic AMP response observed in control cells after 20 min of PGE1 exposure did not occur in retinoic acid-treated cells, and the EQ50 values for PGE, were reduced from ∼240 to 14 nM after retinoic acid treatment. The increased sensitivity to PGE was associated with an increase of high-affinity PGE1 binding sites, whereas the Gs coupling proteins and adenylyl cyclase were not measurably affected. A similar enhancement of the PGE1-cyclic AMP response by retinoic acid was also observed in two additional human neuroblastoma cell lines tested, Kelly and IMR-32, suggesting that up-regulation of the prostaglandin response by retinoic acid is common among neuroblastoma cells. The ability of neuroblastoma cells to elevate cyclic AMP levels upon prostaglandin stimulation could modulate differentiation therapy with retinoic acid in vivo.

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